Chronic myelogenous leukemia (CML) results from malignant transformation of a hematopoietic stem cell. Malignant cells in CML are characterized by the t (9; 22) translocation resulting in the BCR/ABL gene rearrangement. The BCR/ABL protein has constitutively activated protein-tyrosine kinase activity, which is essential for transformation in CML. STI571 (STI, Gleevec), an inhibitor of the BCR/ABL tyrosine kinase, has shown a high degree of activity in all stages of CML in early clinical studies. However, a significant proportion of patients treated with STI do not achieve cytogenetic responses. Moreover, for patients who achieve cytogenetic responses following STI therapy, it is not known whether responses to STI will be durable and result in prolongation of survival. Our preliminary studies indicate that persistent BCR/ABL positive progenitor cells can be detected even in responsive patients in complete cytogenetic remission, indicating that they may be at risk for relapse. We hypothesize that lack of cytogenetic response to STI treatment will correlate with in vitro observations of reduced inhibition of leukemic progenitor growth and reduced suppression of BCR/ABL activated signaling mechanisms by STI. We further hypothesize that the burden of persistent malignant progenitors in patients in cytogenetic response following STI treatment will predict for durability of response. We will determine the relationship between cytogenetic response or lack of response to STI treatment and laboratory assessments of STI-induced inhibition of leukemic progenitor growth and BCR/ABL signaling activities (Specific Aim 1). Development of predictors of non-responsiveness may allow upfront identification of patients requiring alternative treatment approaches. We will also determine the relationship between persistent malignant progenitors in patients with cytogenetic responses to STI and durability of response and risk of relapse, and investigate mechanisms underlying persistence of malignant progenitors (Specific Aim 2). These studies will determine the efficacy of STI in targeting malignant primitive hematopoietic progenitors and may lead to the development of surrogate markers for long-term response. The long-term goal of these studies is to allow optimal use of STI, alone or in combination, in the treatment of CML and improve overall outcomes of treatment.